Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention.

INTRODUCTION: Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure--a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development. METHODS AND ANALYSIS: In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians' discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year. ETHICS AND DISSEMINATION: PIT was approved by NRES Committee North West-Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018. TRIAL REGISTRATION NUMBER: ISRCTN04240319; NCT01604005; Pre-results.

Integrated positron emission tomography-computed tomography does not accurately stage intrathoracic disease of patients undergoing trimodality therapy for malignant pleural mesothelioma.

INTRODUCTION: The results of trimodality therapy for malignant pleural mesothelioma (MPM) are related to stage. Staging can be carried out by computed tomography (CT), magnetic resonance imaging and fluorodeoxyglucose positron emission tomography (FDG-PET), but all modalities suffer from limitations. We investigated whether integrated PET-CT improved the intrathoracic staging of patients undergoing trimodality therapy for MPM. METHODS: Twenty consecutive patients [18 male, median age 62 years (range 52-68)] who underwent 24 PET-CT scans prior to extrapleural pneumonectomy (EPP) as part of trimodality therapy for MPM were reviewed. The intrathoracic stage of MPM on PET-CT was compared with the pathological stage following examination of the resected specimen. Patients excluded from radical surgery due to metastatic disease were not studied here. RESULTS: PET-CT was performed a median of 119 days (range 2-229) prior to EPP. 16 scans were performed after talc pleurodesis. Nine scans were performed following chemotherapy. PET-CT correctly identified the T stage in 3 patients, overstaged 4 and understaged 17. Six scans failed to identify disease that later proved to be pT4. Nine patients were found to have pN2 disease; PET-CT identified N2 disease with a sensitivity of 11.1 %, specificity of 93 % and accuracy of 66 %. Previous talc pleurodesis did not alter the accuracy of PET-CT staging. CONCLUSIONS: In one of the few studies of integrated PET-CT in MPM that has complete pathological correlation we have shown that PET-CT does not accurately identify advanced tumor stage (T4) or mediastinal nodal disease (N2). The role of PET-CT staging prior to EPP lies outside the affected hemithorax.

Videothoracoscopic excision of mediastinal tumors and cysts using the harmonic scalpel.

OBJECTIVE: The aim of this study was to evaluate the safety and reliability of the harmonic scalpel for performing VATS excisions of mediastinal tumors and cysts. METHODS: We have prospectively studied 19 cases presenting with a mediastinal tumor or cyst operated on consecutively since January 2003. RESULTS: We performed 10 left-sided and 9 right-sided VATS procedures; the mean age at operation was 50 +/- 15 years. Two masses were in the anterior mediastinum, 5 in the middle mediastinum and 12 in the posterior mediastinum. One patient required conversion to a minithoracotomy for bleeding. The maximum tumor diameter was 38 +/- 14 mm and the maximum cyst dimension was 55 +/- 20 mm. The mean operating time was 66 +/- 28 min. Three patients experienced minor complications. The postoperative hospital stay was 3.5 +/- 1.7 days, and we had no mortality. Histopathology revealed 1 esophageal leiomyosarcoma, 1 Langerhans cell histiocytosis X, 1 hamartoma, 5 schwannomas, 1 neurofibroma, 1 malignant peripheral nerve sheath tumor, 1 reactive lymphadenopathy, 1 tuberculous lymphadenopathy, 1 cystic hygroma, 2 bronchogenic cysts, 2 foregut cysts, 1 thymic cyst, and 1 pleuropericardial cyst. There has been no recurrence of tumor or cyst on follow-up. CONCLUSIONS: Videothoracoscopic excision of mediastinal tumors and cysts can be safely performed using the harmonic scalpel with a low morbidity and mortality.

A prospective randomized controlled trial of suction versus non-suction to the under-water seal drains following lung resection.

OBJECTIVE: Practice varies as to whether or not suction is applied to under-water seal drains following lung surgery. We tested the null hypothesis that there is no difference with respect to air leak duration. METHODS: Patients undergoing thoracotomy or video assisted thoracoscopic surgery for lobectomy or wedge resection had either low-pressure suction or no suction applied to their underwater seal bottles postoperatively. Patients were allocated using minimization, a method of unbiased allocation ensuring balance between the arms of a trial with respect to known or suspected confounding factors. The trial was powered for duration of air leak. If an air leak persisted on the 7th post-operative day, the surgeon determined further management. Kaplan-Meier survival analysis of air leak duration and a log rank test were performed on an intention-to-treat basis, with observations censored at 144h (6 complete days). RESULTS: Of the 254 patients that entered the trial, data were available for analysis for 239 (123 no-suction and 116 suction). There was no significant difference in the cumulative persistence of air leaks between the two groups (P=0.62) and inspection of the Kaplan-Meier curves suggests that any difference is negligible. CONCLUSIONS: Applying suction to the underwater seal drains following lung surgery makes no difference in terms of air leak duration. In the light of this finding we have adopted a uniform policy of no suction being applied to the underwater seal, from the time of surgery, unless a specific clinical judgment is made to use it. The anticipated gains are that this will reduce work and cost and aid mobilization.

TREK-1, a K+ channel involved in neuroprotection and general anesthesia.

TREK-1 is a two-pore-domain background potassium channel expressed throughout the central nervous system. It is opened by polyunsaturated fatty acids and lysophospholipids. It is inhibited by neurotransmitters that produce an increase in intracellular cAMP and by those that activate the Gq protein pathway. TREK-1 is also activated by volatile anesthetics and has been suggested to be an important target in the action of these drugs. Using mice with a disrupted TREK-1 gene, we now show that TREK-1 has an important role in neuroprotection against epilepsy and brain and spinal chord ischemia. Trek1-/- mice display an increased sensitivity to ischemia and epilepsy. Neuroprotection by polyunsaturated fatty acids, which is impressive in Trek1+/+ mice, disappears in Trek1-/- mice indicating a central role of TREK-1 in this process. Trek1-/- mice are also resistant to anesthesia by volatile anesthetics. TREK-1 emerges as a potential innovative target for developing new therapeutic agents for neurology and anesthesiology.

[A serious complication of sternal puncture: penetrating injury of the ascending thoracic aorta]. / Une complication grave de la ponction sternale: la plaie de l'aorte thoracique ascendante.

INTRODUCTION: Penetrating thoracic aorta wounds are rare but responsible for a high mortality when medical and surgical management is delayed. OBSERVATION: We report the case of a 71 year-old patient with malignant lymphoma who sustained an accidental penetrating injury of the ascending thoracic aorta while undergoing trephine biopsy of the sternum. He was successfully treated with emergency sternotomy and aortic suture-repair. CONCLUSION: This case report highlights the limits of sternal trephine biopsy, notably in patients whose bones are weakened by a malignant haematological process, and proposes preventive measures in order to avoid accidents.

[Videothoracospy in thoracic trauma and penetrating injuries]. / La vidéothoracoscopie dans les traumatismes et plaies du thorax.

Videothoracoscopy represents a valid and useful approach in some patients with blunt chest trauma or penetrating thoracic injury. This technique has been validated for the treatment of clotted hemothorax or posttraumatic empyema, traumatic chylothorax, traumatic pneumothorax, in patients with hemodynamic stability. Moreover, it is probably the most reliable technique for the diagnosis of diaphragmatic injury. It is also useful for the extraction of intrathoracic projectiles and foreign bodies. This technique might be useful in hemodynamically stable patients with continued bleeding or for the exploration of patients with penetrating injury in the cardiac area, although straightforward data are lacking to confirm those indications. Thoracotomy or median sternotomy remain indicated in patients with hemodynamic instability or those that cannot tolerate lateral decubitus position or one-lung ventilation. Performing video-surgery in the trauma setting require expertise in both video-assisted thoracic surgery and chest trauma management. The contra-indications to videothoracoscopy and indications for converting the procedure to an open thoracotomy should be perfectly known by surgeons performing video-assisted thoracic surgery in the trauma setting. Conversion to thoracotomy or median sternotomy should be performed without delay whenever needed to avoid blood loss and achieve an adequate procedure.

The role of videothoracoscopy in management of precordial thoracic penetrating injuries.

OBJECTIVES: To report on the value of diagnostic videothoracoscopy in patients with possible penetrating cardiac wounds. METHODS: Thirteen patients admitted over a 4 year period with hemodynamic stability and a penetrating injury in cardiac proximity had exploratory videothoracoscopy. All data related to those patients were retrospectively reviewed. RESULTS: Eighty-five percent of patients had videothoracoscopy within 8 h of trauma. In most cases (eight of 13), operations were performed on patients in the supine position with the chest slightly rotated. Nine patients had a left hemothorax, five had pulmonary lacerations and five had a bleeding parietal vessel. Pericardial exploration was achieved either by direct vision (nine patients), or by the performance of a pericardial window (four patients). Acute hemopericardium related to a cardiac wound was diagnosed in two patients. Procedures included evacuation of clotted hemothorax (six patients), stapling of pulmonary laceration (four patients), and electrocoagulation of bleeding parietal vessel (four patients). Four patients required conversion to thoracotomy: two for repair of a cardiac wound, one for adequate exposure of the pericardium and one for ligation of a bleeding intercostal artery. The mean operative time was 37+/-23 min. Two patients experienced postoperative complications (coagulopathy, subcutaneous emphysema) and the in-hospital mortality was 0%. The mean hospital stay was 10+/-4 days. CONCLUSIONS: In the hands of an experienced surgeon, videothoracoscopy may represent a valid alternative to subxiphoid pericardial window in patients with hemodynamic stability and a suspected cardiac wound. Videothoracoscopy can rule out a cardiac injury and allows for the performance of associated procedures such as diaphragm assessment/repair, evacuation of clotted hemothorax, hemostasis of parietal vessels or pulmonary laceration and removal of projectiles.

Characterization of effects of endothelin-1 on the L-type Ca2+ current in human atrial myocytes.

The effects of endothelin-1 (ET-1) on the L-type Ca2+ current (I(Ca)) were examined in whole cell patch-clamped human atrial myocytes. Depending on the initial current density, ET-1 (10 nM) increased the amplitude of I(Ca) by 99 +/- 7% or decreased it by 33 +/- 2%. The stimulatory effect predominated on current of low density (2.3 +/- 0.2 pA/pF), whereas I(Ca) of higher density (5.8 +/- 0.3 pA/pF) was inhibited by ET-1. After I(Ca) stimulation by 1 microM isoproterenol, ET-1 always inhibited the current by 32 +/- 7% (P < 0.05), an effect that was suppressed by pretreating myocytes with pertussis toxin. Atrial natriuretic peptide (ANP) inhibited I(Ca) (41 +/- 3%) by reducing intracellular cAMP concentration. In ANP-treated myocytes, the stimulatory effect of ET-1 on I(Ca) predominated (52 +/- 7%). The inhibitory effect of ET-1 on I(Ca) was blocked by the ET(A) antagonist BQ-123, whereas the stimulatory effect was suppressed by the ET(B) agonist BQ-788. We conclude that ET-1 has opposite effects on I(Ca) depending on the baseline amplitude of current, and both subtype ET receptors are implicated in the signal transduction pathways.

The effects of FK506 on neurologic and histopathologic outcome after transient spinal cord ischemia induced by aortic cross-clamping in rats.

UNLABELLED: Spinal cord injury is a devastating complication of thoracoabdominal aortic surgery. We investigated the effect of the immunosuppressant FK506, a macrolide antibiotic demonstrated to have neuroprotective effects in cerebral ischemia models, in a rat model of transient spinal cord ischemia. Spinal cord ischemia was induced in anesthetized rats by using direct aortic arch plus left subclavian artery cross-clamping through a limited thoracotomy. Experimental groups were as follows: sham-operation; control, receiving only vehicle; FK506 A, receiving FK506 (1 mg/kg IV) before clamping; and FK506 B, receiving FK506 (1 mg/kg IV) at the onset of reperfusion. Neurologic status was assessed at 24 h and then daily up to 96 h with a 0 to 6 scale (0, normal function; 6, severe paraplegia). Rats were randomly killed at 24, 48, or 96 h, and spinal cords were harvested for histopathology. Physiologic variables did not differ significantly among experimental groups. All control rats suffered severe and definitive paraplegia. FK506-treated rats had significantly better neurologic outcome compared with control. Histopathologic analysis disclosed severe injury in the lumbar gray matter of all control rats, whereas most FK506-treated rats had less injury. These data suggest that FK506 can improve neurologic recovery and attenuate spinal cord injury induced by transient thoracic aortic cross-clamping. IMPLICATIONS: A single dose-injection of the immunosuppressant FK506 significantly improved neurologic outcome and attenuated spinal cord injury induced by transient thoracic aortic cross-clamping in the rat.

Cumulative inactivation of the outward potassium current: a likely mechanism underlying electrical memory in human atrial myocytes.

The influence of the mode of cell stimulation on the outward K+ current (I(o)) was studied in whole-cell patch-clamped human atrial myocytes. Acceleration of the rate of membrane depolarization at 1 Hz or during prolonged 5-s test pulses at 0.1 Hz increased the rate and extent of I(o) inactivation, resulting in enhanced inactivating (4.9+/-0.6 v 6.3+/-0.7 pA/pF) and suppressed maintained (5.9+/-1.2 v 3.2+/-0.3 pA/pF) current components. These alterations were associated with a leftward shift of the voltage-dependency of I(o), and persisted on returning to a control depolarization protocol (750-ms test pulses delivered at 0.1 Hz). The effects of increasing external K+ concentrations (40 m m) on the kinetics of I(o) were more pronounced following both rapid and prolonged depolarization (changes in I(t)/I(o)caused by 40 m m K+: 8.9+/-3.5% v 15.5+/-3.1% before and after prolonged depolarization; and 9.2+/-1.2% v 15.4+/-1.7% before and after rapid depolarization). The phosphatase inhibitor, okadaic acid, enhanced the effect of rapid and prolonged depolarization on I(o)whereas the inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMK-II) with KN-62 or KN-93, or by intracellular application of the autocamtide-2-related inhibitory peptide, suppressed it. In conclusion, rapid and prolonged membrane depolarization both cause a cumulative increase in the rate and extent of I(o)inactivation. This process involves slow potassium channel inactivation mechanisms, is regulated by CaMK-II, and may contribute to the electrical memory of the atrial myocardium.

Pulmonary resection for Mycobacterium xenopi pulmonary infection.

BACKGROUND: Results of medical therapy for Mycobacterium xenopi pulmonary infection remain unreliable. Pulmonary resection may be beneficial to patients whose disease is localized and who can tolerate a resectional operation. METHODS: Eighteen patients underwent pulmonary resection between 1991 and 2000: 14 men and 4 women, with a mean age of 50 +/- 12 years (range 27 to 68 years). Indications for operation were either therapeutic (n = 9) or diagnostic (n = 9). Four patients received antimycobacterial chemotherapy before their operation and 2 patients were HIV positive. RESULTS: Therapeutic procedures included completion pneumonectomy (n = 1), lobectomy (n = 6), segmentectomy (n = 1), and bilateral wedge resection (n = 1). Diagnostic procedures included lobectomy (n = 1) and wedge resection (n = 8). Complete resection could be achieved in 15 patients (83%). There was no in-hospital mortality. Postoperative complications included prolonged air leak (5 of 18 patients, 27.7%) and pleural effusion requiring insertion of a new chest tube (3 of 18 patients, 16.6%). Mean hospital stay was 14 +/- 8 days. Follow-up was 100% complete. Eleven patients received antimycobacterial chemotherapy for 4 to 24 months, postoperatively. Late mortality was 11% and was unrelated to progression of mycobacterial disease. After the operation, the sputum remained positive in only 2 patients (11%) with incomplete resections. Fourteen patients were asymptomatic with no relapse at a mean follow-up of 38 +/- 22 months (range 85 to 13 months). CONCLUSIONS: Resection represents an important adjunct to chemotherapy for the treatment of M. xenopi pulmonary disease. In the setting of localized nodular or cavitary disease, failure to respond to medical therapy, relapse after treatment discontinuation, coexistent aspergilloma or polymicrobial contamination, or patient intolerance of medical therapy, pulmonary resection can be undertaken with acceptable morbidity and mortality.

Anesthetic concentrations of riluzole inhibit neuronal nitric oxide synthase activity, but not expression, in the rat hippocampus.

We hypothesized that anesthetic dose of riluzole, an inhibitor of glutamate neurotransmission, may affect the activity and/or expression of neuronal NOS (nNOS). Riluzole, N(G)-nitro-L-arginine-methyl ester (L-NAME) and 7-nitro indazole (7-NI) produced a concentration-related inhibition of nNOS activity in vitro. Riluzole competed with 7-NI for inhibition of nNOS activity, but had no effect on nNOS or endothelial NOS (eNOS) protein expression. Also, nNOS activity was significantly decreased in riluzole-anesthetized rats (40 mg kg(-1) i.p., -32+/-6% from controls, P<0.05). Therefore, blockade of nNOS activity may be involved in the anesthetic effects of riluzole in vivo.

Primary spontaneous pneumothorax: one-stage treatment by bilateral videothoracoscopy.

BACKGROUND: The goal of the study was to report our 7-year experience with single-stage bilateral videothoracoscopy for bleb excision and pleural abrasion in patients suffering primary spontaneous pneumothorax. METHODS: From November 1992 through June 1999, 12 men were operated on in our department. Preoperative chest computed tomographic scans were obtained for all patients. Operative indications included simultaneous bilateral pneumothorax (n = 2), contralateral recurrence (n = 1), ipsilateral recurrence with contralateral blebs or bullae, and job restrictions (n = 9). RESULTS: Mean age at operation was 26+/-6 years. All patients had multiple blebs or bullae located in upper lobes, and 4 patients (33%) had pleural adhesions. All blebs or bullae were resected at operation. The mean number of staple cartridges was 5 per patient (range, 3 to 8). All patients had bilateral pleurabrasion. There were no perioperative complications and no conversion to thoracotomy. The mean operative time was 168+/-17 minutes (range, 140 to 190 minutes). The mean drainage time was 5 days (range, 4 to 26 days) and the mean hospital stay was 7.7+/-1.4 days for 11 of 12 patients. Postoperative complications included prolonged air leak (16.5%), incomplete lung reexpansion (25%), and pleural effusion (8.5%). One patient required reoperation on the right side through transaxillary thoracotomy within 1 month of videothoracoscopy for pleurodesis failure. Follow-up was 100% complete. Mean follow-up is 50+/-34 months (range, 9 to 88 months) and no patient has had recurrence of pneumothorax. All patients except one returned to full occupational activity within 5 weeks of surgery. CONCLUSIONS: Single-stage bilateral videothoracoscopy for bilateral bleb excision and pleurabrasion is a safe procedure that does not result in major complications and provides excellent long-term results. This approach could be considered in young patients with bilateral primary spontaneous pneumothorax, or in those requiring radical therapy for the prevention of ipsilateral and contralateral recurrences.